Methamphetamine (METH) abuse afects aproximately 1.2 million individuals nationwide and is characterized by a range of compulsive behaviors, including preoccupation with obtaining the drug, compulsive seeking and taking of the drug, and a loss of control of drug intake. Experimental animals exhibit similar compulsive behaviors when exposed to extended access to METH self-administration. Compulsivity in rodent models can be defined as excessive patterns of drug seeking and taking behavior, including escalation of drug intake, elevated progresive ratio (PR) breakpoints, and increased levels of METH-primed reinstatement. (Kitamura et. al, 2006, Wee et. al, 2007, Wee et. al, unpublished results). The kappa opioid receptor (KOR) and its ligand, prodynorphin, are known to be involved in the central nervous system effects of psychostimulants (see Wee and Koob, 2010 for review). Dynorphins produce dysphoric effects in animals and humans and have been hypothesized to mediate negative emotional states associated with withdrawal from drugs of abuse. However, the direct contribution of the KOR system to the emergence of compulsive behaviors associated with extended access to METH self-administration remains unclear. Preliminary evidence from our laboratory shows that pretreatment with the selective, long-lasting KOR antagonist norbinaltorphimine (NorBNI) injected systemically or directly into the nucleus accumbens (NAc) shell prior to escalation training prevents the escalation of METH intake and reverses elevated PR breakpoints in animals with a history of extended access to METH self-administration. Therefore, the goal of this proposal will be to characterize the role of prodynorphin/KOR in both the emergence and persistence of compulsive METH taking and seeking. To achieve this goal, we will determine whether NorBNI has the ability to reverse the escalation of intake and elevated PR breakpoints associated with extended aces to METH self-administration. Next, we will characterize the expression prodynorphin and activation of KOR signaling in response to extended access to METH self-administration. Then, using c-fos-LacZ transgenic rats and the Daun02 inactivation method, we will identify and selectively inactivate the distinct neuronal ensembles that are activated by extended access to METH self-administration, determining which areas are responsible for driving compulsive METH seeking and taking behaviors. Finally, we will use novel rAAV viral-vectors to selectively knockdown and overexpress prodynorphin in candidate regions to causally link the expression and activity of the endogenous prodynorphin system to compulsive taking and seeking of METH. These studies will specifically assess the role of the dynorphin/KOR system in the expression of compulsive METH taking and seeking. Linking dynorphin/KOR interactions to the compulsive taking and seeking of METH will establish the KOR system as a viable therapeutic target for chronically-relapsing METH abuse.